Lung Epithelial CCAAT/Enhancer-binding Protein-β Is Necessary for the Integrity of Inflammatory Responses to Cigarette Smoke

Didon, Lukas; Barton, Jenny L.; Roos, Abraham B.; Gaschler, Gordon J.; Bauer, Carla M. T.; Berg, Tove; Stämpfli, Martin R.; Nord, Magnus

doi:10.1164/rccm.201007-1113oc

Cited by 32 publications

(41 citation statements)

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“…Embryos were also heterozygous for the Rosa26 allele (ROSA26-Sor tm1Sor/þ ) that harbor the b-galactosidase gene (lacZ) (Soriano, 1999). LacZ was expressed in all lung epithelial cells in all SFTPC-Cre þ offspring whereas it was totally absent in the SFTPC-Cre À mice, as previously demonstrated (Didon et al, 2011). All genotypes were observed at expected Mendelian ratios.…”

Section: Generation Of Mice With a Lung Epithelial-specific Disruptiomentioning

confidence: 89%

“…To test whether C/EBPa and C/EBPb have overlapping roles in regulating lung epithelial gene expression in vivo, mice with a lung-specific disruption of the genes encoding C/EBPa (Cebpa DLE mice), C/EBPb (Cebpb DLE mice), or C/ EBPa and C/EBPb (Cebpa DLE ; Cebpb DLE mice) were produced by SFTPC-Cre-mediated excision, as previously described (Lee et al, 1997;Kwan, 2002;Okubo et al, 2005;Didon et al, 2011). Embryos were also heterozygous for the Rosa26 allele (ROSA26-Sor tm1Sor/þ ) that harbor the b-galactosidase gene (lacZ) (Soriano, 1999).…”

Section: Generation Of Mice With a Lung Epithelial-specific Disruptiomentioning

confidence: 99%

“…Following the identification of the CCAAT/enhancer-binding proteins (C/ EBPs) by McKnight and colleagues, a key role for this group of transcription factors has been demonstrated in the regulation of pulmonary gene expression (Cassel et al, 2000a(Cassel et al, ,b, 2002McKnight, 2001;Cassel and Nord, 2003;Didon et al, 2011). Of the six family members, C/EBPa, C/EBPb, and C/ EBPd are enriched in the lung (Cassel and Nord, 2003;Berg et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…C/EBPb plays a pivotal role in differentiation of myeloid cells, skin, and adipose tissue (Natsuka et al, 1992;Tanaka et al, 1997;Sterneck et al, 2005;Guerzoni et al, 2006) and in contrast to C/EBPa is thought to promote proliferation (Ramji and Foka, 2002). In addition, C/EBPb is important for the respiratory system by regulating the expression of both inflammatory and lung-specific genes (Cassel et al, 2000a(Cassel et al, , 2002Didon et al, 2011). However, C/EBPb-deficient mice display no lung abnormalities during organogenesis (Tanaka et al, 1997;Didon et al, 2011), suggesting that C/ EBPb is not required for differentiation and development of the lung or that other transcription factors may functionally replace the deleted C/EBPb.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, C/EBPb is important for the respiratory system by regulating the expression of both inflammatory and lung-specific genes (Cassel et al, 2000a(Cassel et al, , 2002Didon et al, 2011). However, C/EBPb-deficient mice display no lung abnormalities during organogenesis (Tanaka et al, 1997;Didon et al, 2011), suggesting that C/ EBPb is not required for differentiation and development of the lung or that other transcription factors may functionally replace the deleted C/EBPb. Since the lung-enriched C/EBPs bind to virtually identical DNA-sequences, functional replacement of C/EBPb by C/ EBPa could serve to explain the lack of pulmonary phenotype in mice lacking C/EBPb and, vice versa, functional replacement of C/EBPa by C/EBPb could possibly explain why some mice lacking C/EBPa specifically in the lung epithelium survive until adulthood.…”

Section: Introductionmentioning

confidence: 99%

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Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ

Roos

Berg

Barton

et al. 2012

Developmental Dynamics

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Background: CCAAT/enhancer‐binding protein (C/EBP)α is crucial for lung development and differentiation of the pulmonary epithelium. Conversely, no lung defects have been observed in C/EBPβ‐deficient mice, although C/EBPβ trans‐activate pulmonary genes by binding to virtually identical DNA‐sequences as C/EBPα. Thus, the pulmonary phenotype of mice lacking C/EBPβ could be explained by functional replacement with C/EBPα. We investigated whether C/EBPα and C/EBPβ have overlapping functions in regulating lung epithelial differentiation during organogenesis. Epithelial differentiation was assessed in mice with a lung epithelial–specific (SFTPC‐Cre‐mediated) deletion of C/EBPα (CebpaΔLE), C/EBPβ (CebpbΔLE), or both genes (CebpaΔLE; CebpbΔLE). Results: Both CebpaΔLE mice and CebpaΔLE; CebpbΔLE mice demonstrated severe pulmonary immaturity compared to wild‐type littermates, while no differences in lung histology or epithelial differentiation were observed in CebpbΔLE mice. In contrast to CebpaΔLE mice, CebpaΔLE; CebpbΔLE mice also displayed undifferentiated Clara cells with markedly impaired protein and mRNA expression of Clara cell secretory protein (SCGB1A1), compared to wild‐type littermates. In addition, ectopic mucus‐producing cells were observed in the conducting airways of CebpaΔLE; CebpbΔLE mice. Conclusions: Our findings demonstrate that C/EBPα and C/EBPβ play pivotal, and partly overlapping roles in determining airway epithelial differentiation, with possible implications for tissue regeneration in lung homeostasis and disease. Developmental Dynamics 241:911–923, 2012. © 2012 Wiley Periodicals, Inc.

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Section: Generation Of Mice With a Lung Epithelial-specific Disruptiomentioning

confidence: 89%

Section: Generation Of Mice With a Lung Epithelial-specific Disruptiomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ

Roos

Berg

Barton

et al. 2012

Developmental Dynamics

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Transcriptional profiling and targeted proteomics reveals common molecular changes associated with cigarette smoke-induced lung emphysema development in five susceptible mouse strains

et al. 2015

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BackgroundMouse models are useful for studying cigarette smoke (CS)-induced chronic pulmonary pathologies such as lung emphysema. To enhance translation of large-scale omics data from mechanistic studies into pathophysiological changes, we have developed computational tools based on reverse causal reasoning (RCR).ObjectiveIn the present study we applied a systems biology approach leveraging RCR to identify molecular mechanistic explanations of pathophysiological changes associated with CS-induced lung emphysema in susceptible mice.Methods The lung transcriptomes of five mouse models (C57BL/6, ApoE−/−, A/J, CD1, and Nrf2−/−) were analyzed following 5–7 months of CS exposure.Results We predicted 39 molecular changes mostly related to inflammatory processes including known key emphysema drivers such as NF-κB and TLR4 signaling, and increased levels of TNF-α, CSF2, and several interleukins. More importantly, RCR predicted potential molecular mechanisms that are less well-established, including increased transcriptional activity of PU.1, STAT1, C/EBP, FOXM1, YY1, and N-COR, and reduced protein abundance of ITGB6 and CFTR. We corroborated several predictions using targeted proteomic approaches, demonstrating increased abundance of CSF2, C/EBPα, C/EBPβ, PU.1, BRCA1, and STAT1.Conclusion These systems biology-derived candidate mechanisms common to susceptible mouse models may enhance understanding of CS-induced molecular processes underlying emphysema development in mice and their relevancy for human chronic obstructive pulmonary disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00011-015-0820-2) contains supplementary material, which is available to authorized users.

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CCAAT/Enhancer-Binding Protein δ Is a Critical Mediator of Lipopolysaccharide-Induced Acute Lung Injury

Yan

Johnson

Tang

et al. 2013

The American Journal of Pathology

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Although inflammation plays a central role in the pathogenesis of acute lung injury, the molecular mechanisms underlying inflammatory responses in acute lung injury are poorly understood, and therapeutic options remain limited. CCAAT/enhancer-binding proteins, C/EBPβ and C/EBPδ, are expressed in the lung and have been implicated in the regulation of inflammatory mediators. However, their functions in lung pathobiological characteristics are not well characterized. Herein, we show that C/EBPβ and C/EBPδ are activated in mouse lung after intrapulmonary deposition of lipopolysaccharide (LPS). Mice carrying a targeted deletion of the C/EBPδ gene displayed significant attenuation of the lung permeability index (lung vascular leak of albumin), lung neutrophil accumulation (myeloperoxidase activity), and neutrophils in bronchial alveolar lavage fluids compared with wild-type mice. These phenotypes were consistent with morphological evaluation of lung, which showed reduced inflammatory cell influx and minimal intra-alveolar hemorrhage. Moreover, mutant mice expressed considerably less tumor necrosis factor-α, IL-6, and macrophage inflammatory protein-2 in bronchial alveolar lavage fluids in LPS-injured lung compared with wild-type mice. In contrast, C/EBPβ deficiency had no effect on LPS-induced lung injury. By using small-interfering RNA-mediated knockdown for C/EBPδ, we demonstrate, for the first time to our knowledge, that C/EBPδ plays a critical role for the tumor necrosis factor-α, IL-6, and macrophage inflammatory protein-2 production in LPS-stimulated alveolar macrophages. These findings demonstrate that C/EBPδ, but not C/EBPβ, plays an important role in LPS-induced lung inflammatory responses and injury.

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Lung Epithelial CCAAT/Enhancer-binding Protein-β Is Necessary for the Integrity of Inflammatory Responses to Cigarette Smoke

Abstract: Our data suggest a previously unknown role for C/EBPβ and the airway epithelium in mediating inflammatory and innate immune responses to cigarette smoke.

Cited by 32 publications

References 325 publications

Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ

Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ

Transcriptional profiling and targeted proteomics reveals common molecular changes associated with cigarette smoke-induced lung emphysema development in five susceptible mouse strains

CCAAT/Enhancer-Binding Protein δ Is a Critical Mediator of Lipopolysaccharide-Induced Acute Lung Injury

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